The present invention relates to a sulfonamide-containing heterocyclic compound which is useful as a medicament and to an antiangiogenic effect thereof. Further, it relates to an antitumor agent, a cancer metastasis suppressor, a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatic arthritis and a therapeutic agent for hematoma on the basis of an antiangiogenic effect.
It has become clear that there is a close relation between proliferation of cancer and angiogenesis. Thus, when angiogenesis is not generated at the site of cancer, the cancer remains in a state of dormant tumor. However, it has become clarified that, when angiogenesis is generated, oxygen and nutrients in blood are supplied to the tumor whereby proliferation and metastasis of cancer are promoted resulting in a clinically malignant state. Accordingly, it is expected that, when angiogenesis of cancer is suppressed, proliferation and metastasis of cancer can be suppressed. Since angiogenetic vessels are composed of endothelial cells and interstitial cells of the host, target of the antiangiogenic agent is not cancer cells but such normal cells of the host. Because of the fact that the cancer cells are not a direct target, efficacy to the cancer which does not respond to known anticancer agents can be expected as well and, in addition, it is presumed that the possibility of occurrence of tolerant cancer which is a big problem in cancer therapy is little. In addition, angiogenesis is a tumor-specific phenomenon and, in mature individuals, it is limited to the formation of endometrium, etc. accompanied by a menstrual cycle. Accordingly, its adverse effect is thought to be little as compared with known anticancer drugs. Recently, it has been experimentally proved in preclinical tests that antiangiogenic agents are able to suppress and further to reduce the proliferation of cancer in the cancer-transplanted models and that tolerant cancer is not generated and, in clinical tests, the correlation between angiogenesis and malignization of many solid cancers such as breast cancer, prostatic cancer, lung cancer and cancer of the colon has been shown.
In cancer tissues, apoptosis and proliferation of cancer cells continuously occur and it has been known that, depending upon the balance between them, progressive cancer or dormant tumor is resulted. An antiangiogenic agent does not directly kill the cancer cells but cuts off the nutrient sources so that the said balance is inclined to apoptosis inducing dormant tumor or reduction in cancer whereby it is a drug which can be expected to exhibit an excellent effect (prolongation of life, inhibition of recurrence and suppression of metastasis) by a long-term therapy.
In a preclinical stage, there are antiangiogenic agents by various action mechanisms but, since their antitumor effect in a preclinical stage is insufficient, their usefulness in clinical stage is still doubtful and, therefore, there has been a brisk demand for antiangiogenic agents where the effect is reliable.
It has been also known that angiogenesis participates in retinopathy or retinitis. When blood vessel is proliferated in retina, eyesight gets worse and, when progressed, blindness is resulted. Effective therapeutic drugs have been demanded.
In GB 662798, hydroxy- and acyloxy-phenylsulfonylamino-substituted quinoline and quinoxaline are disclosed, but relates to antiviral agents and are different from the present invention. In J. Sci. Ind. Res., sect. B, 21(1962), 3-p-toluenesulfonylamino-8-hydroxyquinoline is disclosed. Though, there is no description relating to an antiangiogenic effect. In JP-A 1-254682, 1,8-naphthylidine and pyrido[2,3-d]pyrimidine derivatives having a substituted sulfonamide are disclosed, but relates to herbicides and are different from the present invention. In JP-A 62-426 and 7-267936, sulfonamidequinoxaline derivatives having antitumor activity are disclosed. Though, there is no description relating to an antiangiogenic effect.
Accordingly, an object of the present invention is to provide a novel sulfonamide-containing heterocyclic compound that has an excellent an antiangiogenic effect and has a different structure from those of conventional antiangiogenic agent. Another object of the present invention is to provide an intermediate of the compound and a pharmaceutical composition containing the compound as an active ingredient.
The present inventors have made intensive investigations for an antiangiogenic agent. As a result, they have found that a novel sulfonamide-containing heterocyclic compound has an excellent antiangiogenic effect and has an excellent effect as a pharmaceutical drug. Thus, they have accomplished the present invention.
Specifically, the present invention provides a sulfonamide-containing heterocyclic compound represented by the formula (I), a pharmacologically acceptable salt thereof or a hydrate of them. 
In the formula:
A is hydrogen atom, a halogen atom, hydroxyl group, a C1-C4 alkyl group or alkoxy group which may be substituted with a halogen atom, cyano group, xe2x80x94(CO)kNR2R3 (wherein, R2 and R3 are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; and k means 0 or 1), a C2-C4 alkenyl group or alkynyl group which may have a substituent, or a phenyl group or phenoxy group which may have a substituent selected from the following group A;
B is an aryl group or monocyclic heteroaryl group which may have a substituent selected from the following group A, or 
(wherein, the ring Q is an aromatic ring which may have one or two nitrogen atoms; the ring M is an unsaturated C5-C12 monocyclic or polycyclic ring which shares a double bond with the ring Q, and the ring may have 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; the ring Q and the ring M may share nitrogen atom with each other; and the ring Q and the ring M may each have a substituent selected from the following group A);
K is a single bond or xe2x80x94(CR4R5)mxe2x80x94 (wherein, R4 and R5 are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group; and m is an integer of 1 or 2);
T, W, X and Y are the same as or different from each other and each means xe2x95x90C(D)xe2x80x94 (wherein D is hydrogen atom, a halogen atom, hydroxyl group, a C1-C4 alkyl group or alkoxy group which may be substituted by a halogen atom, cyano group, xe2x80x94(CO)nNR6R7 (wherein R6 and R7 are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; and n means 0 or 1), or a C2-C4 alkenyl group or alkynyl group which may have a substituent), or nitrogen atom;
U and V are the same as or different from each other and each means xe2x95x90C(D)xe2x80x94 (wherein, D has the same meaning as defined above), nitrogen atom, xe2x80x94CH2xe2x80x94, oxygen atom or xe2x80x94COxe2x80x94;
Z is a single bond or xe2x80x94COxe2x80x94NHxe2x80x94;
R1 is hydrogen atom or a C1-C4 alkyl group; and
 means a single or double bond,
Group A
a halogen atom, hydroxyl group, a C1-C4 alkyl group or alkoxy group which may be substituted by a halogen atom, cyano group, xe2x80x94R8R9N(NH)pxe2x80x94 (wherein R8 and R9 are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; and p means 0 or 1, and R8 and R9 may be combined with the nitrogen atom to which they bound to form a 5- or 6-membered ring which may include nitrogen atom, oxygen atom or sulfur atom and may have a substituent), an aminosulfonyl group which may be substituted with one or two C1-C4 alkyl groups, an optionally substituted C1-C8 acyl group, a C1-C4 alkyl-S(O)s-C1-C4 alkylene group (wherein s means an integer of 0, 1 or 2), a phenylsulfonylamino group which may have a C1-C4 alkyl or a substituent, xe2x80x94(CO)qNR10R11 (wherein R10 and R11 are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with an amino group which may be substituted with a halogen atom or a C1-C4 alkyl group; and q means 0 or 1), or an aryl or heteroaryl group which may have a substituent,
provided that when U is oxygen atom, V means xe2x80x94COxe2x80x94 or xe2x80x94CH2xe2x80x94; when V is oxygen atom, U means xe2x80x94COxe2x80x94 or xe2x80x94CH2xe2x80x94; and the following cases 1) where only one of T, U, V, W, X and Y is nitrogen atom; and A and D are both hydrogen atoms, 2) where T, U, V, W, X and Y are all nitrogen atoms, 3) where Y and W are nitrogen atoms; T, U, V and X are xe2x95x90C(D1)xe2x80x94 (wherein D1 means hydrogen atom, methyl group, a halogen atom, trifluoromethyl group or methoxy group); and Z is a single bond; and A is hydrogen atom, methyl group, a halogen atom, trifluoromethyl group or methoxy group, 4) where W is nitrogen atom; T, U, V, X and Y are xe2x95x90C(D2)xe2x80x94 (wherein D2 means hydrogen atom); K and Z are single bonds; A is hydroxyl group; and B is p-toluenesulfonylamino group, 5) where V and W are nitrogen atoms and 6) where T, V and W are nitrogen atoms are excluded.
The present invention provides a halogen-substituted quinoline compound represented by the following formula: 
(wherein, Y1 and W1 are different from each other and each means nitrogen atom or xe2x95x90C(D3)xe2x80x94 (wherein, D3 is hydrogen atom, a halogen atom, hydroxyl group, a C1-C4 alkyl group or alkoxy group which may be substituted with a halogen atom, cyano group or xe2x80x94(CO)nNR6R7 (wherein, R6 and R7 are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; and n means 0 or 1)); E is a halogen atom, cyano group or a C1-C4 alkyl group which may be substituted with a halogen atom; J is an amino group which may have a protecting group or a carboxyl group which may have a protecting group; G1 is hydrogen atom, a halogen atom, hydroxyl group, a C1-C4 alkyl group or alkoxy group which may be substituted with a halogen atom, cyano group, xe2x80x94(CO)tNR14R15 (wherein, R14 and R15 are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; and t means 0 or 1), or an optionally substituted C2-C4 alkenyl group or alkynyl group which is a production intermediate of the compound represented by the above formula (I), or a salt thereof.
In addition, the present invention provides a process for producing a compound represented by the formula: 
(wherein E1 is a halogen atom; R16 is a carboxyl-protecting group; G2 is hydrogen atom, a halogen atom, hydroxyl group or a C1-C4 alkyl group or alkoxy group which may be substituted with a halogen atom), which comprises the step of reducing a compound represented by the formula: 
(wherein E1 is a halogen atom; E2 is chlorine atom or bromine atom; R16 is a carboxyl-protecting group; G2 is hydrogen atom, a halogen atom, hydroxyl group, or a C1-C4 alkyl group or alkoxy group which may be substituted with a halogen atom) with tin, zinc or iron.
The compound represented by the above formula (IV) is a compound of the above formula (II) wherein Y1 is nitrogen atom; W1 is xe2x95x90CHxe2x80x94; E is a halogen atom; J is a carboxyl group having a protecting group; and G1 is hydrogen atom, a halogen atom, hydroxyl group, or a C1-C4 alkyl group or alkoxy group which may be substituted with a halogen atom.
The present invention provides an antiangiogenic agent, an anti-cancer agent, a cancer metastasis suppressor, a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatic arthritis or a therapeutic agent for hematoma, comprising the sulfonamide-containing heterocyclic compound represented by the above formula (I) a pharmacologically acceptable salt thereof or a hydrate of them, as an active ingredient.
The present invention provides a method for preventing or treating a disease against which an antiangiogenic effect is efficacious for the prevention or treatment of cancer, cancer-metastasis, diabetic retinopathy, rheumatic arthritis or hematoma, by administering a pharmacologically effective amount of the sulfonamide-containing heterocyclic compound represented by the above formula (I), a pharmacologically acceptable salt thereof or a hydrate of them to a patient.
The present invention provides use of the sulfonamide-containing heterocyclic compound represented by the above formula (I), a pharmacologically acceptable salt thereof or a hydrate of them, for producing an antiangiogenic agent, an anti-cancer agent, a cancer metastasis suppressor, a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatic arthritis or a therapeutic agent for hematoma.
In the present invention, the xe2x80x9caromatic ring which may have one or two nitrogen atomsxe2x80x9d in ring Q is an aromatic hydrocarbon or a 6-membered aromatic heterocycle including one or two nitrogen atoms. Examples of such aromatic rings in ring Q are benzene, pyridine, pyrimidine, pyrazine, pyridazine etc. The xe2x80x9cunsaturated C5-C12 monocyclic or polycyclic ring, which may have one to four hetero atoms selected from nitrogen atom, oxygen atom and sulfur atomxe2x80x9d as ring M means an unsaturated monocyclic or polycyclic ring which shares a double bond with ring Q and includes aromatic hydrocarbon rings such as benzene and naphthalene; unsaturated hydrocarbon rings such as cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadienes, cycloheptadienes and cyclooctadienes; and unsaturated heterocyclic rings such as tetrahydropyridine, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine, indole, isoindole, quinoline, isoquinoline, indazolidine, naphthylidine, benzofuran, benzopyran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, pyrrolopyridine, pyridopyrimidine and imidazopyridine. The phrase xe2x80x9cring Q and ring M may share one nitrogen atom with each otherxe2x80x9d means the case where the nitrogen atom is present at the condensation position between the two rings, and such rings include, for example, indazolidine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine and pyrazolo[1,5-a]pyrimidine.
In the present invention, the C1-C4 alkyl group in R1, R4 and R5, and the C1-C4 alkyl group in the C1-C4 alkyl group which may be substituted with a halogen atom in A, D, R1, R2, R3, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, G1, G2 and Group A include linear or branched alkyl groups having 1 to 4 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and tert-butyl group. The phrase xe2x80x9cwhich may be substituted with a halogen atomxe2x80x9d means that each of these alkyl groups may be substituted by a halogen atom(s) selected from fluorine atom, chlorine atom, bromine atom and iodine atom. Such halogen-substituted alkyl groups include, for example, monofluoromethyl group, monochloromethyl group, difluoromethyl group, trifluoromethyl group, 1- or 2-monofluoroethyl group, 1- or 2-monochloroethyl group, 1- or 2-monobromoethyl group, 1,2-difluoroethyl group, 1,2-dichloroethyl group, 1,1,2,2,2-pentafluoroethyl group and 3,3,3-trifluoropropyl group. Among them, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 1- or 2-monofluoroethyl group, 1,2-difluoroethyl group and 1,1,2,2,2-pentafluoroethyl group are preferred.
In the present invention, the C1-C4 alkoxy group in the C1-C4 alkoxy group which may be substituted with a halogen atom in A, D and Group A includes linear or branched alkoxy groups having 1 to 4 carbon atoms, such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butyloxy group, isobutyloxy group, sec-butyloxy group and tert-butyloxy group. The phrase xe2x80x9cwhich may be substituted with a halogen atomxe2x80x9d means that each of these alkoxy groups may be substituted by a halogen atom(s) selected from fluorine atom, chlorine atom, bromine atom and iodine atom. Such halogen-substituted alkoxy groups include, for example, monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 1- or 2-monofluoroethoxy group, 1- or 2-monochloroethoxy group, 1- or 2-monobromoethoxy group, 1,2-difluoroethoxy group, 1,1,2,2,2-pentafluoroethoxy group and 3,3,3-trifluoropropoxy group. Among them, monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 1- or 2-monofluoroethoxy group, 1,2-difluoroethoxy group and 1,1,2,2,2-pentafluoroethoxy group are preferred.
In the present invention, the C2-C4 alkenyl group or alkynyl group in A and D includes alkenyl groups or alkynyl groups having 2 to 4 carbon atoms, such as vinyl group, allyl group, 2- or 3-butenyl group, 1,3-butanedienyl group, ethynyl group, 2-propynyl group, 2-methylethynyl group, and 2- or 3-butynyl group.
The aryl group in B and Group A in the present invention means and includes aromatic hydrocarbon groups such as phenyl group and naphthyl group. The heteroaryl group means and includes monocyclic and polycyclic rings each containing one or more nitrogen atoms, oxygen atoms and sulfur atoms. Such heteroaryl groups include, for example, pyrrolyl, imidazolyl group, pyrazolyl group, triazolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyridyl group, pyrimidyl group, pyrazyl group, indolyl group, indolizinyl group, benzimidazolyl group, benzothiazolyl group, benzoxazolyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group, and phthalazinyl group.
The phrase xe2x80x9cR8 and R9 may be combined with the nitrogen atom to which they bound to form a 5- or 6-membered ring which may include nitrogen atom, oxygen atom or sulfur atomxe2x80x9d in R8 and R9 in the present invention means that R8 and R9 together with the nitrogen atom to which they bound form a ring such as pyrrolidinyl group, piperidinyl group, morpholino group, thiomorpholino group and piperazinyl group.
In the present invention, the C1-C4 alkyl group in the aminosulfonyl group which may be substituted with one or two C1-C4 alkyl groups, an optionally substituted C1-C8 acyl group, the C1-C4 alkyl-S(O)s-C1-C4 alkylene group, C1-C4 alkyl- or phenyl-sulfonylamino group which phenyl group may have a substituent and the C1-C4 alkyl group which may be substituted with an amino group which may be substituted with a halogen atom or a C1-C4 alkyl group in Group A mean and include the same alkyl groups as mentioned above. The alkylene group includes, for example, methylene group, ethylene group, propylene group and butylene group, as well as methylmethylene group, 1- or 2-methylethylene group, 1-, 2- or 3-methylpropylene group and dimethylmethylene group.
The C1-C8 alkanoyl group means, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, benzoyl group etc.
The protecting group in the xe2x80x9camino group which may have a protecting groupxe2x80x9d in J in the present invention is not specifically limited as long as it is generally used as an amino-protecting group in organic synthesis. Such protecting groups include, but are not limited to, benzyloxycarbonyl group, t-butoxycarbonyl group, formyl group, acetyl group, chloroacetyl group, 2,2,2-trichloroethyl group, benzylidene group, benzhydryl group and trityl group. The protecting group in the carboxyl group which may have a protecting group and the carboxy-protecting group in R16 are not specifically limited and can be any protecting groups as long as they are generally used as carboxyl-protecting groups in organic synthesis. Such protecting groups include, but are not limited to, methyl group, ethyl group, propyl group, isopropyl group, t-butyl group, methoxymethyl group, 2,2,2-trichloroethyl group, pivaloyloxymethyl group and benzyl group.
In the present invention, the substituent in the phrase xe2x80x9cwhich may have a substituentxe2x80x9d means and includes the aforementioned halogen atoms, C1-C4 alkyl groups or alkoxy groups which may be substituted with a halogen atom, hydroxyl group, hydroxy-C1-C4 alkyl groups, amino groups which may be substituted with one or two C1-C4 alkyl groups, C2-C4 alkenyl groups or alkynyl groups, cyano group, C1-C8 acyl groups, aminosulfonyl groups which may be substituted with one or two C1-C4 alkyl groups, carboxyl group, C1-C4 alkoxy-carbonyl groups, and carbamoyl groups which may be substituted with one or two C1-C4 alkyl groups.
The sulfonamide-containing heterocyclic compounds represented by the above formula (I) may form salts with acids or bases. The present invention also includes the salts of the compound (I). Such salts with acids include, for example, inorganic acid salts such as hydrochlorate, hydrobromate and sulfate; and salts with an organic acid such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid. Examples of the salt with a base are an inorganic salt such as sodium salt, potassium salt and calcium salt, and that with an organic base such as triethylamine, arginine or lysine.
It goes without saying that the present invention further includes all the optical isomers, if any, as well as a hydrate of these compounds. Further, the compounds which show an antiangiogenic effect produced from the compound of the present invention by subjecting as a result of metabolism such as oxidation, reduction and hydrolysis in vivo are also included. The present invention further includes the compounds which produce the compound of the present invention as a result of metabolism such as oxidation, reduction and hydrolysis in vivo.
The compounds (I) of the present invention can be prepared by various processes. Representative processes of them are as follows.
1) When Z is a Single Bond 
In the formula, A, B, T, U, V, W, X and T have the same meanings as defined above.
Specifically, the objective compounds can be prepared by allowing a sulfonic acid represented by the formula (V) or a reactive derivative thereof to react with a compound represented by the formula (VI).
Such reactive derivatives of the sulfonic acid (V) include, for example, generally used reactive derivatives such as sulfonyl halides, sulfonyl anhydrides and N-sulfonylimidazolide. Among them, sulfonyl halides are typically preferred. Solvents for use in the reaction are not specifically limited, but are preferably solvents that dissolve material substances and are inert to these materials. Such solvents include pyridine, tetrahydrofuran, dioxane, benzene, ethyl ether, dichloromethane, dimethylformamide, and mixtures of these solvents. When an acid liberates accompanied with a proceeding reaction as in the case when a sulfonyl halide is used in the reaction, the reaction is preferably performed in the presence of an appropriate deacidification agent. Therefore, in such a case, pyridine and other basic solvents are typically preferably used. When a neutral solvent is used, an alkali metal carbonate, an organic tertiary amine or another basic substance may be added to the reaction system. Solvents that can be used herein are not limited to those mentioned above. The reaction generally proceeds at room temperature, but the reaction system may be cooled or heated according to necessity. The reaction time can optionally be selected depending on the types of material compounds and the reaction temperature and is generally from 10 minutes to 20 hours.
When the amino group or hydroxyl group of the resulting product is protected, a sulfonamide derivative (VII) having a free hydroxyl group or amino group can be obtained by subjecting the product to treatment with an acid, treatment with a base, catalytic reduction and other conventional deprotecting procedures according to necessity.
2) When Z is xe2x80x94COxe2x80x94NHxe2x80x94
In the formula, L is chlorine atom or bromine atom; R17 is a C1-C4 alkyl group or a benzyl group; and A, B, T, U, V, W, X and Y have the same meanings as defined above.
The target compound can be prepared by allowing an isocyanate compound represented by the formula (VIII) to react with sulfonamide compound represented by the formula (IX).
The reaction is generally performed in water or a water-miscible inert solvent such as tetrahydrofuran and acetone in the presence of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide and sodium hydride. The reaction is performed at a temperature from 0xc2x0 C. to 100xc2x0 C. and preferably from about 20xc2x0 C. to about 30xc2x0 C.
Alternatively, the target compound is prepared by a process in which the sulfonamide represented by the formula (IX) is allowed to react with a haloformate represented by the formula (XIII) to give a carbamate represented by the formula (XII), and the resulting carbamate is allowed to react with an amine represented by the formula (XI).
The reaction between the sulfonamide represented by the formula (IX) and the haloformate represented by the formula (XIII) is performed in an inert solvent such as acetone, tetrahydrofuran and methyl ethyl ketone in the presence of an acid scavenger such as potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide. A reaction temperature may range from about 30xc2x0 C. to reflux temperature. Subsequently, the reaction between the carbamate represented by the formula (XII) and the amine represented by the formula (XI) is performed by heating in an inert high-boiling solvent such as dioxane, toluene and diglyme at temperatures ranging from about 50xc2x0 C. to reflux temperature.
The amine compounds represented by the formula (VI) or (XI) are materials for the sulfonamide- or sulfonylurea-containing heterocyclic compounds of the present invention and can be prepared by combinations of conventional procedures.
For example, quinoline and isoquinoline derivatives can be prepared according to the following production processes. 
In the formula, A, E2, G2 and R16 have the same meanings as defined above; and R18 is a C1-C4 alkyl group or a benzyl group. 
In the formula, A and G2 have the same meanings as defined above. 
In the formula, R18 has the same meaning as defined above; and R19 is a C1-C4 alkyl group. 
In the formula, R18 and E2 have the same meanings as defined above; R20 and R21 are each hydrogen atom or a C1-C4 alkyl group; R22 is a C1-C4 alkoxy group, an optionally substituted phenoxy group or phenyl group, cyano group, or an amino group which may be substituted with one or two C1-C4 alkyl groups; and E3 is hydrogen atom, a halogen atom, a C1-C4 alkoxy group, an optionally substituted phenoxy group or phenyl group, cyano group, or an amino group which may be substituted with one or two C1-C4 alkyl groups.
When the compounds of the present invention are used as pharmaceutical drugs, they are administered to a patient orally or parentally. The dose varies depending on the severity of symptoms, age, sex, body weight and sensitivity of the patient, medication method, administration time period, administration interval, characteristics, dispensing and type of the resulting pharmaceutical preparation, the type of the active ingredient etc., and is not specifically limited. The dose is generally from 10 to 6000 mg, preferably from about 50 to about 4000 mg and more preferably from 100 to 3000 mg per day per adult. The drug is administered to a subject one to three times a day.
To prepare oral solid preparations, fillers and, where necessary, other additives such as binders, disintegrators, lubricants, coloring agents and flavoring agents are added to a base component, and the resulting mixture is formed into tablets, coated tablets, granules, fine granules, powders, capsules etc. according to a conventional procedure.
Such fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide. The binders include, for example, polyvinyl alcohol, ethyl cellulose, methylcellulose, gum arabic, hydroxypropylcellulose and hydroxypropylmethylcellulose. The lubricants include magnesium stearate, talc and silica. The coloring agents include those permitted to use in pharmaceutical drugs. The flavoring agents include cocoa powder, menthol, aromatic powder, peppermint oil, borneol and powdered cinnamon bark. These tablets and granules can be coated with sugar, gelatin or other coating substances according to necessity.
To prepare injections, additives such as pH adjusting agents, buffers, suspending agents, solubilizing agents, stabilizers, isotonicity and preservatives are added to the base component, and the resulting mixture is formed into intravenous injections, subcutaneous injections or intramuscular injections according to a conventional procedure. Where necessary, the injections are formed into freeze-dried preparations.
Such suspending agents include methylcellulose, polysorbate 80, hydroxyethylcellulose, gum arabic, powdered tragacanth, sodium carboxymethylcellulose and polyoxyethylene sorbitan monolaurate.
The solubilizing agents include polyoxyethylene hydrogenated caster oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol and caster oil fatty acid ethyl esters.
The stabilizers include sodium sulfite and sodium metasulfite, and the preservatives include, for example, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
The effect of the compounds of the present invention will be illustrated with reference to Pharmacological Experimental Example below.
Pharmacological Experimental Example 1, Antiangiogenic Effect
The inhibition degree of angiogenesis which was observed when aorta pieces of rat were incubated in collagen was defined as an antiangiogenic effect. That is, the thoracic aorta excised from male rat of Sprague-Dawley strain (10-12 weeks age) was washed with a Hanks"" solution (Gibco BRL, Gaithersburg, USA) so that fat tissues around there were removed minutely. The aorta was incised to prepare pieces of 2 mm square and they were allowed to stand in a 24-well plate holding the endothelial cells upside. Then, 500 xcexcl of neutralized Type I collagen (Cell Matrix Type I-A; manufactured by Nitta Gelatin) were poured over each well and allowed to stand at room temperature for about 20 minutes in a clean bench to solidify the gel. After confirming that the gel was solidified, 500 xcexcl of MCDB 131 medium (manufactured by Chlorella Kogyo) were added thereto followed by incubating in a CO2 incubator (5% CO2) at 37xc2x0 C. On the next day, the culture medium was exchanged with 500 xcexcl of MCDB 131 medium containing the test compound and the incubation was continued. After three days, the medium was again exchanged with 500 xcexcl of MCDB 131 medium containing the test compound and, at the stage of the 7th day from the initiation of addition of the test compound, numbers of capillaries formed around the aorta were counted under a microscope. The solution containing the test compound was prepared in a three-fold dilution system where 10 xcexcg/ml was the highest concentration.
Inhibiting rate was calculated from the following formula and 50% inhibiting concentration (IC50) for each test compound was determined.
Inhibiting Rate (%)=(Cxe2x88x92T)/Cx100
C: Numbers of capillaries when no compound was added
T: Numbers of capillaries when a compound was added Table 1